Scfa colonic composition

ABSTRACT

The present invention is directed to a colonic composition including a core having at least one short chain fatty acid selected from the group consisting of butyrate, acetate and propionate, and combinations thereof, or a pharmaceutically acceptable salt or ester thereof; wherein at least one of acetate or propionate is present in the core; and at least one digestion-resistant layer covering the core, the digestion-resistant layer disintegrating in the colon. The present invention is also directed to methods of treatment using the above composition.

BACKGROUND

The present invention is directed to a colonic composition comprisingshort chain fatty acids (SCFAs), and more specifically to a compositiontargeting the colon with selected SCFAs, the composition including acore comprising select SCFAs and a digestion-resistant layer coveringthe core.

There is growing knowledge regarding the beneficial effects of SCFA inthe colon. SCFA are naturally formed by colon microorganisms fermentingpolysaccharides that are non-digestible by humans. The three main SCFAof interest are acetate, propionate, and butyrate. Acetate acts as asubstrate for hepatic de novo lipogenesis via acetyl-coA and fatty acidsynthase. Propionate down regulates lipogenesis through inhibition of3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA), the rate-limitingenzyme in cholesterol synthesis. Butyrate is an important energy sourcefor colonic mucosa and also controls gene expression through theinhibition of histone deacetylase.

SCFA also regulate gut hormones including peptide YY (PYY) andglucagon-like peptide (GLP), which play a role in secretion of digestiveenzymes and satiety. SCFA (especially propionate and butyrate) bind toFFA2 and FFA3 receptors in intestinal L cells.

Orally consumed SCFA are readily absorbed in the small intestine andnever reach the colon. Administration of non-digestible carbohydratessuch as oligo-fructose can provide SCFA to the colon via microorganismfermentation, but results in the production of all three SCFA to variousdegrees.

SUMMARY

In one embodiment, the present invention is directed to a coloniccomposition, comprising a core comprising at least one short chain fattyacid selected from the group consisting of butyrate, acetate andpropionate, and combinations thereof, or a pharmaceutically acceptablesalt or ester thereof; wherein at least one of acetate or propionate ispresent in the core; and at least one digestion-resistant layer coveringthe core, the digestion-resistant layer disintegrating in the colon.

In another embodiment, the present invention is directed to a method oftreating a patient suffering from a weight loss disorder, a conditionthat benefits from reduction of cholesterol, a condition of the colon,or diabetes or increased risk for developing diabetes, the methodcomprising administering to the patient a dosage form containing atherapeutically effective amount of the colonic composition of theinvention.

DETAILED DESCRIPTION

As indicated above, the present invention is directed to coloniccompositions and related methods that utilize short chain fatty acids(SCFAs) and their derivatives to provide health benefits or treatment ofdiseases or conditions in the colon. In one embodiment, the compositionof the invention includes a core comprising at least one short chainfatty acid selected from the group consisting of butyrate, acetate andpropionate, and combinations thereof, or a salt or ester thereof,wherein at least one of acetate or propionate is present in the core;and at least one digestion-resistant layer covering the core, whereinthe digestion-resistant layer disintegrates in the colon. Each of thesecomponents is discussed in more detail below.

The colonic composition of the present invention comprises a corecontaining at least one SCFA selected from butyrate, acetate orpropionate. Each of these SCFAs may take any suitable chemical formwhich may be advantageously selected for therapeutic or compositionalpurposes, for example, acid form, salt form, ester form, and the like.According to the invention, the core may include each of the SCFAsindividually or in any combination, however at least either acetate orpropionate must be included in the core formulation.

In some embodiments the at least one SCFA can be present as apharmaceutically acceptable salt. “Pharmaceutically acceptable salts” asdefined herein include derivatives of the disclosed SCFA compoundswherein the parent compound is modified by making non-toxic salts of thecarboxylate group thereof, and further refers to pharmaceuticallyacceptable hydrates, solvates of such compounds, and such salts.Examples of pharmaceutically acceptable salts include, but are notlimited to, mineral or organic acid salts of the carboxylic acid groupof the SCFA. For example, conventional non-toxic acid salts includethose derived from inorganic acids such as hydrochloric, hydrobromic,sulfuric, sulfamic, phosphoric, nitric and the like; and the saltsprepared from organic acids such as acetic, propionic, succinic,glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic,maleic, hydroxylmaleic, phenylacetic, glutamic, benzoic, salicylic,mesylic, esylic, besylic, sulfanilic, 2-acetoxybenzoic, fumaric,toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic,HOOC-(CH₂)_(n)-COOH where n is 0-4, and the like. Lists of additionalsuitable salts may be found, e.g., in Remington's PharmaceuticalSciences, 17th ed., Mack Publishing Company, Easton, Pa., p. 1418(1985). In some embodiments the SCFA can be present as an ester of theSCFA's carboxylic acid with a branched or unbranched alkyl alcohol ofone to 6 carbons. For example, the SCFA can be present as an ethylester, propyl ester, butyl ester, isopropyl ester, t-butyl ester, pentylester, or hexyl ester.

In some embodiments, the core may comprise additional SCFA other thanacetate, propionate or butyrate. Additional SCFAs useful in theinvention include, for example, alkyl monocarboxylic acids, straightchain or branched, of from two to six carbons. Examples of additionalSCFA include isobutyrate, t-butyl carboxylate, pentanoate, hexanoate,and the like. The additional SCFA may be an SCFA substituted with one tothree substituents such as halogen (fluoro, chloro, bromo, iodo), cyano,hydroxy, methoxy, keto, and the like. For example, substituted SCFAsuseful as additional SCFAs include hydroxyacetate, ketopropionate,4,4,4-trifluorobutyrate, and the like.

The core may additionally comprise a pharmaceutically acceptablecarrier. Carriers suitable for use in the core component of theinvention include excipients and diluents, and must be of sufficientlyhigh purity and sufficiently low toxicity to render them suitable foradministration to the patient being treated. The carrier can be inert orit can possess pharmaceutical benefits of its own. The amount of carrieremployed in conjunction with the compound is sufficient to provide apractical quantity of material for administration per unit dose of thecompound.

Classes of carriers include, but are not limited to binders, bufferingagents, coloring agents, diluents, disintegrants, emulsifiers,flavorings, glidants, lubricants, preservatives, stabilizers,surfactants, tableting agents, and wetting agents. Some carriers may belisted in more than one class, for example vegetable oil may be used asa lubricant in some formulations and a diluent in others. Exemplarypharmaceutically acceptable carriers include sugars, starches,celluloses, powdered tragacanth, malt, gelatin, talc, and vegetableoils. Optional active and/or inactive agents may be included in thepharmaceutical compositions, provided that such agents do notsubstantially interfere with the activity of the SCFA and relatedcompounds used in the pharmaceutical compositions.

The colonic composition of the invention includes a digestion-resistantlayer covering the core. “Digestion-resistant layer” as used hereinmeans that a layer is resistant to digestion or degradation in theproximal parts of the gastrointestinal tract (namely mouth, esophagus,stomach and the first two parts of the small intestine) but is degradedin the colon. In a typical digestive process for a human subject,“digestion resistant layer” can mean that the layer remains at least50%, at least 75% or preferably at least 90% intact at the time acomposition comprising the layer reaches the colon. Thedigestion-resistant layer is preferably made of at least one layer ofbiocompatible natural or man-made polymer which. The digestion-resistantlayer is designed to release SCFA core within the lumen of the colon.Disintegration of the digestion-resistant layer may be mediated byenvironmental factors such as a basic pH or digestion by the colonmicrobiome. It may also occur in a time-dependent manner and designed tooccur within hours to days after ingestion. Remnants of thedigestion-resistant layer that are not absorbed through the colon mucosaare designed to be excreted in feces of the user.

Examples of useful materials that may comprise the digestion-resistantlayer include eudragit, hydroxymethylcellulose, chitosan, pectin, guargum, chondroitin sulfate, amylose, alginate, and the like, andcombinations thereof. In some embodiments, at least one digestionresistant layer comprises eudragit, and in some embodiments at least onedigestion-resistant layer comprises hydroxymethylcellulose.

In some embodiments the core may comprise one selected SCFA or acombination of SCFAs. Useful ranges of each of the selected SCFAs rangefrom 0 wt % to 100 wt %, based on the total weight of the SCFAs. Forexample, the combination of SCFAs can be 50 wt % acetate and 50 wt %butyrate, or 10 wt % acetate and 90 wt % butyrate, or 60 wt % propionateand 40 wt % butyrate, based on the total weight of SCFA, among otheracceptable combinations. The selected ratios and weight percents of theSCFA compounds in the invention can be easily determined and selected byone of skill in the art based on the appropriate application.

The weight ratio of the total weight of SCFA to the total weight of thecore may be from 1:50 to 1:10, from 1:10 to 1:5, from 1:5 to 1:2, orfrom 1:2 to 1:1.

The weight ratio of the core to the digestion-resistant layer may befrom 1:10 to 20:1, from 1:10 to 10:1, from 1:5 to 5:1, or from 1:2 to2:1.

The colonic composition of the invention is preferably formulated asunit doses for ease of administration. The amount of SCFA in a unit dosemay be generally varied or adjusted from about 1.0 milligram to about100 milligrams, from about 10 to about 1000 milligrams, or from about1000 to about 3000 milligrams, according to the particular applicationand the potency of the compound. A unit dose may be administered to apatient 1, 2, or 3 or more times per day, depending on the dose requiredfor effective treatment. The actual dosage employed may be varieddepending upon the patient's age, sex, weight and severity of thecondition being treated. The amount of a unit dose may be based on mg ofSCFA per kg of the patient's body weight, or mg/kg. The unit dose for apatient can be from about 0.1 mg/kg to about 10 mg/kg, from about 1 toabout 10 mg/kg, or from about 10 to about 100 mg/kg.

In another embodiment, the dosage form is a tablet, a capsule, or aliquid form.

In another embodiment, treating the patient with the dosage formcomprises providing the dose to the patient through the mouth, a feedingtube, an enterostomy, or per rectum.

In some embodiments of the invention, a colonic composition containingSCFA is ingested by mouth, swallowed and passes through the stomachwhere it remains undigested. The colonic composition then proceeds alongthe small intestine where it is not absorbed. When the coloniccomposition reaches the colon, it loses its digestion-resistant layerand becomes an uncoated core which interacts with the colon content andthe colon wall (mucosa). SCFA that comprise the core can be absorbedthrough the colon wall (mucosa).

The composition of the invention is useful for treating patientssuffering from conditions of the colon or conditions benefitting fromreceiving SCFA through the colon. The invention includes a method oftreating a patient suffering from a weight loss disorder, a conditionthat benefits from reduction of cholesterol, a condition of the colon,or diabetes or increased risk of developing diabetes, comprisesadministering to the patient a dosage form containing a therapeuticallyeffective amount of the above-described colonic composition.

The term “therapeutically effective amount” of a compound of the coloniccomposition of the present invention is defined herein to mean an amounteffective, when administered to a human or non-human patient, to providea therapeutic benefit such as an amelioration of symptoms, e.g., anamount effective to decrease the symptoms of a weight loss disorder,symptoms of a disorder that benefits from reduction of cholesterol, orsymptoms of a disorder associated with a condition of the colon, andincluding an amount sufficient to reduce the above mentioned symptoms.In certain circumstances a patient suffering from the above describeddisorders may not present symptoms. Thus a therapeutically effectiveamount of a compound is also an amount sufficient significantly reducethe detectable level of appropriate biomarkers in the patient's blood,serum, other bodily fluids, or tissues. For example, a therapeuticallyeffective amount to treat a disorder that benefits from reduction ofcholesterol can be an amount sufficient to significantly reduce bloodLDL cholesterol. The invention also includes, in certain embodiments,using compounds of the colonic composition of the present invention inprophylactic treatment and therapeutic treatment. In the context ofprophylactic or preventative treatment a “therapeutically effectiveamount” is an amount sufficient to significantly decrease the treatedpatient's risk of suffering from the above described disorders. Forexample, prophylactic treatment may be administered when a subject willknowingly be exposed to treatment that is associated with a risk ofweight loss, such as major surgery. A significant reduction is anydetectable negative change that is statistically significant in astandard parametric test of statistical significance such as Student'sT-test, where p<0.05.

In one embodiment a patient suffering from a weight loss disorder can betreated with the colonic composition of the present invention preferablycomprising acetate. Acetate is believed to up-regulate lipogenesis. Thisapproach can be used as part of a refeeding or anabolic program inpatients with anorexia nervosa or those following prolongedhospitalization, chemotherapy, major surgery, or chronic disease. Thisapproach can be used in patients with cachexia (weight loss) due tochronic disease such as malignancy, rheumatologic disease or heartfailure. The weight loss disorder can further include disorders that areexpected to lead to weight loss, such as malnutrition or a catabolicstate, even if actual weight loss has not yet occurred.

In another embodiment a patient suffering from a condition that benefitsfrom reduction of cholesterol can be treated with the coloniccomposition of the present invention preferably comprising propionate.Cholesterol is associated with atherosclerosis including coronary arterydisease, cerebrovascular disease, renal artery disease and peripheralvascular disease. It is well established that lower levels of lowdensity lipoproteins (LDL cholesterol) are associated with reducedcardiovascular risk. Moreover, it is established that reducing LDLcholesterol levels by drugs inhibiting the rate-limiting enzyme incholesterol synthesis, HMG CoA-Reductase reduces cardiovascularmorbidity and mortality. Without being bound by theory, it is believedthat propionate inhibits HMG CoA-Reductase and may be accountable forsome of the health benefits associated with fiber consumption. A coloniccomposition of the present invention containing propionate or other SCFAwith similar effects can be used to inhibit cholesterol synthesis and tocontrol cardiovascular risks. One clinical benefit associated with theiruse is the fact they do not affect the absorption of other drugs, asthey are only released to the gastrointestinal lumen distal to wheremost other drugs are absorbed. In some embodiments the patient issuffering from high cholesterol, and in other embodiments the patienthas normal cholesterol but suffers from a condition that benefits fromreduction of cholesterol to below normal levels (such as cardiovasculardisease). As lower cholesterol lowers risk of cardiac events even forhealthy individuals with normal cholesterol levels, in some embodimentstreating a patient suffering from a condition that benefits fromreduction of cholesterol can include treating a healthy person withnormal cholesterol, in order to gain the benefits of cholesterollowering.

In one embodiment, a patient suffering from a condition of the colon canbe treated with the colonic composition of the present inventionpreferably comprising butyrate. Butyrate is an important source ofenergy for the colon mucosa and can provide up to 10% of the totalenergy demand of the body. Some clinical conditions are associated withincreased energy demand of the colon mucosa or with reduced energysupply to the colon mucosa. Some clinical conditions are associated withincreased body energy demand or decreased body energy supply. Thecurrent invention may be used to treat any or all of the aforementionedcondition categories. In some embodiments, the patient is suffering froma condition of the colon, including ischemic colitis, inflammatory boweldisease, colitis from radiation or chemotherapy, typhlitis, or coloncancer.

For example, ischemic colitis is a state of inadequately low bloodsupply to the colon or a portion of it. It usually results from acute orchronic conditions affecting the mesenteric arteries or veins such asatherosclerosis, infarction, embolus, thrombus. Colonic ischemia mayresult from increased venous pressure in the mesenteric or systemicvenous system due to right heart failure or portal hypertension. Thisgroup of diverse clinical conditions may result in abdominal pain,reduced appetite, impaired peristalsis but also in mucosal damage thatis associated with bacterial translocation across it and sepsis orperitonitis. Direct energy supply to the colon mucosa in the form ofSCFA preferably including butyrate may compensate for the inadequatesupply of nutrients to the colonic mucosa through the blood and helpmaintain the function of the colonic mucosa, including water absorptionand protection against bacterial translocation.

Patients following major surgery, especially abdominal surgery, cannotconsume food for a period of time that commonly extends to days becauseof reduced consciousness, ileus and suspected or diagnosed leakinganastomoses. Some patients have decreased appetite and consume fewercalories than their needs. Other severely ill patients are fed throughtotal parenteral nutrition but can still swallow pills or receive pillsthrough a feeding tube or an enterostomy. These patients commonly do notreceive the full amount of nutrients and calories they need, and usingthe colonic composition of the present invention can both maintain thewellness of their colon mucosa and increase their caloric intake.

The turnover rate of cells in the colonic mucosa is high, resulting inhigh metabolic needs. It also accounts for the colon mucosasusceptibility to being damaged by radiation therapy and chemotherapy,which are at times intended to treat cancer elsewhere but cause damageto the colon as an adverse effect. Colitis from radiation orchemotherapy may result in severe pain, diarrhea and inflammation.Damage to the mucosal barrier may lead to bacterial translocation andsepsis. When chemotherapy-induced neutropenia is present, the mucosalbarrier is further compromised, potentially resulting in severeinflammation around the colon (typhlitis) and in an increased risk ofbacteremia. In fact, most of the cases of bacteremia or fungemia inneutropenic patients are the result of translocation of microorganismsacross the colon mucosa.

In one embodiment, treatment of a patient with the colonic compositionof the present invention preferably comprising butyrate, can provide theenergy needed for the colon mucosa to regenerate faster followingradiation or chemotherapy injury. It may thus reduce the risk ofdisseminated infection as a result of microbial translocation across thecolon mucosa.

In another embodiment, treatment of a patient using the coloniccomposition of the present invention preferably comprising butyrate canbe used wherein the condition of the colon is associated with highermetabolic needs of the colon mucosa such as inflammatory bowel disease(e.g. Crohn's disease or ulcerative colitis) or graft versus hostdisease involving the colon.

In another embodiment, treatment of a patient using the coloniccomposition of the present invention preferably comprising butyrate canbe used wherein the condition of the colon is associated with resectionof the gallbladder, wherein SCFA are formed in the colon to a lesserextent in those patients because of reduced concentration of bile saltsreaching the colon. The colonic composition of the present inventionpreferably comprising butyrate can also be used to provide energy to thecolon mucosa, especially when blood supply is compromised (e.g. ischemiccolitis, heart failure) or the metabolic needs are increased (e.g. afterchemotherapy or radiation therapy). In this context, it may prevent oralleviate radiation colitis and typhlitis.

It has been suggested that at least part of the therapeutic effect ofmetformin (a drug used in the prevention and treatment of diabetes) ismediated by alteration of SCFA production in the colon, morespecifically alteration of butyrate levels in the colon. In oneembodiment, treatment of a patient using the colonic composition of thepresent invention preferably comprising butyrate can be used to improveglycemic control when a patient has diabetes or is at risk of developingdiabetes.

In another embodiment, the core comprises propionate.

In another embodiment, the core comprises acetate

In another embodiment, the at least one digestion resistant layercomprises eudragit.

In another embodiment the at least one digestion resistant layercomprises hydroxymethylcellulose.

In another embodiment the at least one digestion resistant layercomprises a composition selected from the group consisting of Chitosan,pectin, guar gum, chondroitin sulfate, amylose, alginate, andcombinations thereof

In another embodiment, a colonic composition includes any or all of thenaturally occurring SCFA formed within the human colon, namelypropionate, butyrate or acetate, and includes at least one of propionateor acetate.

In another embodiment, a colonic composition may include at least onenaturally occurring SCFA that is not normally found within the humancolon.

In yet another embodiment, the colonic composition may include at leastone artificially synthesized SCFA which has therapeutic effects on thehuman body.

In another embodiment, the patient is suffering from a weight lossdisorder.

In another embodiment, the weight loss disorder is anorexia nervosa,malnutrition, or weight loss following prolonged hospitalization,chemotherapy, major surgery, or chronic disease.

In another embodiment, the weight loss disorder is anorexia nervosa.

In another embodiment, the at least one short chain fatty acid comprisesacetate.

In another embodiment, the patient is suffering from a condition thatbenefits from reduction of cholesterol.

In another embodiment, the patient is suffering from high cholesterol.

In another embodiment, the patient has normal cholesterol, but suffersfrom a condition that benefits from reduction of cholesterol to belownormal levels.

In another embodiment, the condition is a cardiovascular disease.

In another embodiment, the at least one short chain fatty acid comprisespropionate.

In another embodiment, the patient is suffering from diabetes orincreased risk of diabetes, or from a condition of the colon, includingischemic colitis, inflammatory bowel disease, colitis from radiation orchemotherapy, typhlitis, or colon cancer.

In another embodiment, the at least one short chain fatty acid comprisesbutyrate.

Unless otherwise specified, all % values herein are weight % (wt %),based on the total weight of the colonic composition.

The descriptions of the various embodiments of the present inventionhave been presented for purposes of illustration, but are not intendedto be exhaustive or limited to the embodiments disclosed. Manymodifications and variations will be apparent to those of ordinary skillin the art without departing from the scope and spirit of the describedembodiments. The terminology used herein was chosen to best explain theprinciples of the embodiments, the practical application or technicalimprovement over technologies found in the marketplace, or to enableothers of ordinary skill in the art to understand the embodimentsdisclosed herein.

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 7. A method of treating a patient suffering from a weightloss disorder, a condition that benefits from reduction of cholesterol,a condition of a colon, or diabetes or increased risk of diabetes, themethod comprising: administering to said patient a dosage formcontaining a therapeutically effective amount of a colonic composition,said composition consisting of: a core consisting of at least one shortchain fatty acid selected from the group consisting of butyrate, acetateand propionate, and combinations thereof, or a pharmaceuticallyacceptable salt or ester thereof; wherein at least one of acetate orpropionate is present in said core; and at least one digestion-resistantlayer covering said core, said digestion-resistant layer disintegratingin the colon; and releasing the core within the lumen of the colon. 8.The method of claim 7 wherein the dosage form is a tablet, a capsule, ora liquid form.
 9. The method of claim 7 wherein treating the patientwith the dosage form comprises providing the dose to the patient throughthe mouth, a feeding tube, an enterostomy, or per rectum.
 10. The methodof claim 7, wherein the patient is suffering from a weight lossdisorder.
 11. The method of claim 10, wherein the weight loss disorderis anorexia nervosa, malnutrition, or weight loss following prolongedhospitalization, chemotherapy, major surgery, or chronic disease. 12.The method of claim 11, wherein the weight loss disorder is anorexianervosa.
 13. The method of claim 7, wherein the at least one short chainfatty acid comprises acetate.
 14. The method of claim 7, wherein thepatient is suffering from a condition that benefits from reduction ofcholesterol.
 15. The method of claim 14, wherein the patient issuffering from high cholesterol.
 16. The method of claim 14, wherein thepatient has normal cholesterol, but suffers from a condition thatbenefits from reduction of cholesterol to below normal levels.
 17. Themethod of claim 16, wherein the condition is a cardiovascular disease.18. The method of claim 7, wherein the at least one short chain fattyacid comprises propionate.
 19. The method of claim 7, wherein thepatient is suffering from diabetes or increased risk of diabetes, orfrom a condition of the colon, including ischemic colitis, inflammatorybowel disease, colitis from radiation or chemotherapy, typhlitis, orcolon cancer.
 20. The method of claim 19, wherein the at least one shortchain fatty acid comprises butyrate.